Miriam E. Tucker

May 08, 2013

PHOENIX — Testosterone replacement reverses insulin resistance in hypogonadal men with type 2 diabetes, preliminary data suggest. The findings, from a randomized trial in 81 men, were reported by Paresh Dandona, MD, PhD, head of the division of endocrinology, diabetes, and metabolism at the University of Buffalo, State University of New York, at the American Association of Clinical Endocrinologists 2013 Scientific & Clinical Congress last week.

"Hypogonadotropic hypogonadism [HH] in type 2 diabetes is a factor related to insulin resistance and may be contributing to it. Administration of testosterone over a period of 6 months largely reverses that state of insulin resistance," said Dr. Dandona.

Although glycemic control did not change as a result of the testosterone therapy, other metabolic parameters did. "What is important is that you're replacing fat with lean body mass, also improving insulin sensitivity, and reducing the inflammatory background," he told Medscape Medical News.

He added, "Right now, doctors aren't even screening. The important thing is to measure [testosterone] and see... Once you get there, comprehensively deal with the individual."

But session moderator Dr. Edward Horton, MD, from the Joslin Diabetes Center, Boston, Massachusetts, told Medscape Medical News that he's not yet convinced that testosterone replacement is the answer for all of these patients. "My own feeling is I want to see more long-term outcome data showing what the beneficial effects are," said Dr. Horton.

Insulin Sensitivity Improved by 25% With Testosterone

Of the 81 men with type 2 diabetes recruited for the study, 39 had HH, defined as free testosterone concentrations of less than 5 ng/dL with normal or low luteinizing hormone (LH) and follicle-stimulating hormone (FSH).

At baseline, the hypogonadal men had a mean age of 54, higher body mass indexes (BMIs) (39 vs 34 kg/m2, P = .002), and lower levels of total testosterone (252 vs 508 ng/mL, P < .001), free testosterone (4.3 vs 7.6 ng/dL, P < .001), calculated free testosterone (5.4 vs 96 ng/dL, P < .001), and sex-hormone–binding globulin (26 vs 38 nmol/L, P = .008).

Body composition, as measured by dual-energy X-ray absorptiometry (DEXA), also differed significantly between the groups at baseline, with the hypogonadal men having significantly greater total fat mass (P < .001) and significantly less total lean mass (P = .002), as well as significantly greater fat mass in the arms, legs, and trunk and lower lean mass in the legs.

Even after adjustment for age and fat mass, insulin sensitivity was significantly reduced in the hypogonadal men, by about 25% (P = .017).

"So clearly, hypogonadism is associated with a state of insulin resistance," Dr. Dandona noted.

The men with HH were randomized to receive 250-mg intramuscular testosterone or placebo (1-mL saline) every 2 weeks for 24 weeks. The intramuscular-testosterone dose was adjusted to maintain free testosterone concentrations at 11 to 13 ng/dL, the mid-normal range for young healthy men.

Of the 29 men with HH who have completed the 24-week study so far, the 15 who received testosterone replacement experienced significant increases from baseline in total testosterone (562 vs 256 ng/dL, P = .001), free testosterone (12.4 vs 4.1 ng/dL, P < .001), and calculated free testosterone (15.1 vs 5.4 ng/dL, P < .001). In contrast, no significant differences were seen at 24 weeks among the 14 men who received saline, Dr. Dandona reported.

Glycated hemoglobin (HbA1c) actually rose slightly in both groups, from 6.6% to 7.1% in the testosterone group (P = .05) and from 6.7% to 7.2% in the placebo patients (P = .14). The study did not attempt to manipulate glucose control, which was managed by the patients' own physicians, Dr. Dandona noted.

At 24 weeks, insulin sensitivity was increased by about 25% with testosterone supplementation (P = .01), vs no significant change with placebo (P = .75).

Exchange of Fat for Lean Body Mass

"What this tells me is that the insulin sensitivity is improving even if you mismanage the glycemic part… I don't expect testosterone to change glucose significantly, although in the background you have improved insulin sensitivity," Dr. Dandona told Medscape Medical News.

BMI did not change significantly in either group. However, the testosterone group had significant increases in total lean mass, of about 2 kg (P = .004) with a concurrent 2-kg drop in total fat mass (P = .02); no changes were seen in the placebo group.

"So clearly, while the BMI does not change, you have an exchange of adiposity for lean body mass, which is something that favors insulin sensitivity and of course favors overall health and cardiovascular risks," Dr. Dandona said.

Other significant changes with testosterone treatment included reductions in serum levels of insulin, homeostasis model assessment-insulin resistance (HOMA-IR), free fatty acids, C-reactive protein, leptin, and mRNA expression of several genes associated with insulin resistance (all P < .05).

Consider Treatment With Testosterone?

Dr. Dandona told Medscape Medical News that he has probably treated more men with testosterone replacement than anyone else in the world and therefore, "I've seen enough benefit from treating low testosterone, so mine is a biased view... I have been converted just through sheer experience."

Dr. Horton does not disagree. "One of the messages is that HH is a more common syndrome than previously recognized, and we should be considering testosterone-replacement therapy when we find it," he told Medscape Medical News.

However, he added: "We know insulin resistance is associated with low-grade inflammation. There is tremendous interest in the field on the role of chronic inflammation and the various biomarkers that probably are contributing to atherosclerosis and long-term cardiovascular disease. This is a hypothesis that testosterone-replacement therapy will benefit these markers and ultimately reduce cardiovascular disease.

"But I'm not 100% convinced…that we have enough data yet to really know that. I think the pendulum will swing, like the whole issue of hormone-replacement therapy in women… It's still an area under active investigation," he concluded.

This study was funded by the National Institute of Diabetes, Digestive and Kidney Diseases and the American Diabetes Association. Dr. Dandona is a consultant or speaker for and/or has research grants from Novo Nordisk, Merck, Bristol Myers-Squibb, Eli Lilly, Sanofi, and Boehringer Ingelheim. Dr. Horton has received research grants from and/or served on advisory boards for Amylin, Eli Lilly, Merck, Bristol Myers-Squibb, AstraZeneca, Takeda, Janssen, and Boston Biomedical Associates.

American Association of Clinical Endocrinologists 2013 Scientific & Clinical Congress. Abstract 280, presented May 2, 2013.